The Mayo Clinic SPORE in Pancreatic Cancer has built one of the best environments for translational researchers who are committed to the goal of reducing the incidence and mortality of this devastating malignancy. Our aims are to: 1) Provide the scientific leadership and organization to sustain and support outstanding translational pancreatic cancer research;2) Provide the organizational infrastructure to facilitate communication and promote interactions among SPORE investigators and the larger research community;3) Provide resources to develop innovative research projects in translational pancreatic cancer research;4) Foster career development in translational pancreatic cancer research;and 5) Assure excellence of research through a rigorous internal review process of the SPORE research programs and projects, with periodic review and support from a panel of outstanding external advisors. Over the past funding period, tremendous progress has been made in creating an infrastructure that nurtures the conduct of innovative research and interdisciplinary interactions, and which has attracted committed scientists and clinicians. Mayo Clinic sees -570 patients with pancreatic cancer annually, constituting 1.5% of all pancreatic cancer cases in the U.S. Four cores (Administrative Core, Biostatistics Core, Clinical Research Core, and Tissue Core) will support research in the SPORE. Broad institutional support for investigators and the research infrastructure will facilitate the translation of scientific discovery to the patient. Project 1, Regulation of Pancreatic Cancer Cell Proliferation and Survival by GSK-3 (led by Drs. Billadeau &Kim) will study how GSK-3P is over-expressed in pancreatic cancer, evaluate it as a novel chemotherapeutic target in mouse models, and study a GSK-3 inhibitor in patients. Project 2, Pancreatic Cancer-associated Diabetes (PaCDM): Pathogenesis and Biomarkers (led by Drs. Chari &Klee) will examine if B-cell dysfunction is an early defect in PaCDM, determine if adrenomedullin is the mediator of PaCDM: and develop and validate a predictive model for PaC among new-onset diabetics. Project 3, Hedgehog and EGF Pathway Interaction: A Novel Approach For A Multi-Target Therapy in Pancreatic Cancer (led by Drs. Fernandez-Zapico &Erlichman) will study the mechanisms underlying the HH-EGF pathway interaction;determine response to HH-EGF combined therapy with new imaging markers, and perform a phase l/ll trial. Project 4, Development of Immune-Modulating Therapies Delivered Directly to the Pancreatic Tumor Site (led by Drs. Mukherjee &Alberts) will optimize a MUC1-based vaccine in the PDA.MUC1 Tg mouse;assess immune status of pancreatic cancer patients to determine if the immune tolerance and surveillance mechanisms observed in the PDA mouse appropriately resemble human patients;and conduct a Phase I trial utilizing a MUC1-peptide based vaccine. In summary, this competing renewal application will continue our strong trajectory of facilitating translational research in pancreatic cancer.